Low-Dose Tramadol as an Off-Label Antidepressant:A Data Mining Analysis from the Patients’ Perspective (2024)

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ACS Pharmacol Transl Sci. 2020 Dec 11; 3(6): 1293–1303.

Published online 2020 Oct 29. doi:10.1021/acsptsci.0c00132

PMCID: PMC7737323

PMID: 33344902

John A. Bumpus*

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Associated Data

Supplementary Materials

Abstract

Objectives: The purposeof this analysis was to assess,from the patients’ perspective, the effectiveness and relativesafety of tramadol as an off-label antidepressant and to determineif patients’ views and experiences are consistent with thebiomedical literature. Method: A data mining approachwas used to analyze databases available at drugs.com. Results: Tramadol was reported to bean effective or very effective antidepressant by 94.6% of patients(123/130) who provided ratings submitted to User Reviews forTramadol to Treat Depression (https://www.drugs.com/comments/tramadol/for-depression.html). When compared to 34 other antidepressants in the database titled Drugs Used to treat Depression (https://www.drugs.com/condition/depression.html), for which there were ≥100 individual reviews for each drug,tramadol was rated as being the most effective (effectiveness rating= 9.1/10). Phenelzine (effectiveness rating = 8.7/10) was the onlyother antidepressant having ≥100 individual reviews coupledwith a very high (8.0–10.0) effectiveness rating. Eleven patientsreported significant symptoms of withdrawal upon cessation of tramadol,and five patients reported loss or reduction of libido as a side effect.Most (57/72, 79.2%) patients who reported a dose consumed experiencedrelief from depression at low therapeutic doses (25–150 mg/day).Fourteen patients reported taking this antidepressant for 5–10years, and four patients reported taking tramadol for 10 or more years.Results demonstrated that most patients’ comments and beliefsare consistent with the biomedical literature. Conclusions: Patients’ reviews coupled with a survey of the biomedicalliterature indicate that at low therapeutic doses in the absence ofinteractions with other drugs, adult patients found tramadol to bea generally safe, effective, and fast-acting medication for relieffrom depression.

Keywords: tramadol, off-label, antidepressant, depression, data mining, opioid

Tramadol, a widely prescribedanalgesic, is a racemic (1:1) mixture of (1R,2R)- and (1S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol)(a.k.a. (1R,2R)- and (1S,2S)-tramadol).

Low-Dose Tramadol as an Off-Label Antidepressant:A Data Mining Analysis from the Patients’ Perspective (4)

The article of commerce is the hydrochloridesalt of thisracemate. Its effectiveness as an analgesic is due mainly to the abilityof (1R,2R)-tramadol and its morepotent metabolite, the corresponding (1R,2R)-O-desmethyltramadol (known as M1), tobind to μ-opioid receptors and function as weak, yet effective,agonists of these receptors in the central nervous system. The parentracemate also functions as both norepinephrine and serotonin reuptakeinhibitors. Thus, tramadol may be described as a mixed-function centrallyactive analgesic. Tramadol addiction has been reported in individualswho have consumed high doses for prolonged periods. However, addictionappears to be less problematic than for high-affinity opioids suchas morphine, heroin, oxycontin, and fentanyl.¹

In addition to its use as an analgesic, there is substantialevidencethat tramadol is an effective antidepressant. This evidence is presentedand/or summarized in over 50 citations in the peer-reviewed biomedicalliterature in animal models,²⁻³² in humans,³³⁻⁵³ in the patent literature,⁵⁴⁻⁵⁷ and in reports provided by patients.⁵⁸⁻⁶⁰ The World Health Organization (WHO) Expert Committee on Drug Dependencepublished a comprehensive review of the chemistry, biochemistry, andbiomedical aspects of tramadol in 2018.¹ Much of the background information and review material presentedhere concerning this medication is from this reference and referencestherein.

The overall objectives of this analysis are to: (1)document, fromthe patients’ perspective, the effectiveness of tramadol asan off-label antidepressant; (2) determine if patients’ experiencesand beliefs about this medication are consistent with the peer-reviewedbiomedical literature; and (3) assess the relative safety of low-dosetramadol.

Methodology

Selection of the Medical Social Media WebsiteUsed in This Analysis

The informational website https://www.drugs.com/(58) was selected for this analysis. Embeddedwithin this website are two databases:^59,60 one containinga discussion forum specifically addressing tramadol as an off-labelmedication for depression,⁵⁹ and the othercomparing tramadol to 101 other antidepressants.⁶⁰ Although the United States Food and Drug Administration(US FDA) recommends⁶¹ this website, commentsby individual respondents, descriptions of their experiences, andopinions posted in the discussion forum are solely those of the respondents.Similarly, the analyses of these comments and drug comparisons aresolely those of the author. Therefore, individual comments by respondents,their descriptions of experiences and opinions, and the author’sanalysis claim no FDA endorsem*nt.

Analytical Approach

The discussion forum/database regardingthe effectiveness of tramadol as an antidepressant on the drugs.com website is titled User Reviews for Tramadol to treat Depression.⁵⁹ This discussion forum contained 139 reviewsby patients and descriptions of their experiences with this drug aswell as their ratings of its effectiveness as an antidepressant. Thisdiscussion forum was last accessed on 09/8/2020, immediately beforethis manuscript was submitted for publication. Three respondents submittedtwo reviews each. Thus, the total number of patients involved in thisanalysis was 136. For the three respondents who submitted two reviewseach, both effectiveness ratings were included in these analyses.

Data Mining

Data mining typically refers to the processof using sophisticated computer algorithms to abstract new informationfrom very large data sets. Here a simpler data mining analysis wasused to abstract information from a relatively small data set whoseanalysis was manageable using an MS Word table, manual data entry,and visual analysis. Tramadol reviews addressing depression whichappear on the drugs.com website⁵⁹ were accessed, each respondent was assigneda patient number in order of their submission starting with the firstpatient respondent who accessed this website on 6/17/2012. A listof anonymous patient respondents and all of their respective uneditedcomments and effectiveness ratings were placed in an MS Word table(Table S-1). Available numeric data andinformation regarding other descriptors and queries were examined,and appropriate information was manually recorded. Using the “Find”function, several keywords, numbers, and short phrases were used tolocate information relevant to this analysis in the comments in Table S-1. Depression, antidepressant, addiction,dependence, pill, tablet, tolerance, and suicide are examples of thekeywords used. A complete list of keywords used accompanies Table S-1.

Limitations and Strengthsof This Analysis

Tramadolhas undergone rigorous investigation and has received FDA approvalfor use as an analgesic.⁶² The use of tramadolas an antidepressant has not received such scrutiny. Nevertheless,its ability to function as an antidepressant has been well-documented.²⁻⁶⁰

Although no substitute for large-scale, well-designed investigations,patient-reported experiences are important. Thus, evidence presentedby patients on medical social media websites such as that reportedhere⁵⁸⁻⁶⁰ should not be dismissed or overlooked as merely anecdotal.Indeed, comments analyzed here can be regarded as “miniatureor abbreviated case reports” from the perspective of the patient.This type of evidence is generally regarded as less reliable thanpeer-reviewed studies. However, such evidence is considered more robustas the number of reports increase. Even when a large number of similarreports occur, it is still necessary be circ*mspect when interpretingresults. Nevertheless, multiple reports of experiences by patientscoupled with corroborating independent biomedical research resultslends credence to both. In almost all instances, patients’comments and experiences analyzed here are discussed coupled withmutually supportive results reported in the peer-reviewed biomedicalliterature.

The lack of a comprehensive systematic questionnaireor surveyis a limitation. Except for requesting information about the lengthof time patients had taken this medication and the patient’srating of its effectiveness, no other pertinent information was specificallyrequested by the discussion forum. Thus, information shared in thecomments section was that deemed important by the patient.

Athird issue concerns the composition of the patient population.Certainly, the respondents are not a representative sample of thepopulation at large. However, they do represent a population of individualswho have dealt with depression long-term, often over the course ofmany years. With only two possible exceptions (patients #69 and #116),all appear to have used tramadol as a treatment for their depressionand have elected to share their unfiltered, practices, attitudes,and opinions and/or experiences. Rather than a limitation or liability,this is viewed as a major strength of this analysis.

Results

Effectivenessof Tramadol as an Antidepressant

Of 101antidepressants, 34 had ≥100 individual reviews.⁶⁰ Of this group, patients rated tramadol as beingthe most effective, having an average effectiveness rating of 9.1out of 10 (Table 1).Phenelzine (effectiveness rating = 8.7) was the only other antidepressanthaving ≥100 individual reviews coupled with a very effective(8.0–10.0) rating.⁶⁰ When the criteriawas lowered to ≥40 individual reviews (n =52), nine other antidepressants had effectiveness ratings in the 8.0–10.0range. These antidepressants included alprazolam (8.8). methylphenidate(8.8), niacin (8.8), Parnate (8.8), Nardil (8.7), Xanax (8.7), modafinil(8.6), tranylcypromine (8.6), and amitriptyline (8.2). Alprazolamand Xanax, phenelzine and Nardil, and tranylcypromine and Parnateare generic and brand name versions of the same medication, respectively.In each case, the generic and the brand name versions had very similareffectiveness ratings, within 0.2 of each other.⁶⁰ Interestingly, a few pairs of generic and brand name versionshad somewhat greater differences for medications having antidepressanteffectiveness ratings less than 8–10. The greatest differencewas for the two brand names Effexor and Effexor XL and their genericvenlafaxine which had effectiveness ratings of 5.5, 6.7, and 6.1,respectively.

Table 1

Effectiveness Rating of Tramadol toTreat Depression: Comparison with Other Antidepressants Having 40or More Reviews^a^,^b

	antidepressant	numberof reviews	effectiveness rating
1	tramadol (off-label)	139	9.1
2	alprazolam	93	8.8
3	methylphenidate	53	8.8
4	niacin (off-label)	47	8.8
5	Parnate	76	8.8
6	phenelzine	102	8.7
6	Nardil	83	8.7
7	Xanax	74	8.7
8	Modafinil (off-label)	54	8.6
9	tranylcypromine	93	8.6
10	amitriptyline	99	8.2
11	l-methylfolate	122	7.8
12	Wellbutrin	257	7.4
13	Deplin	84	7.4
14	Lamotrigine (off-label)	124	7.3
15	citalopram	654	7.3
16	Remeron	144	7.3
17	Seroquel XL	47	7.3
18	Celexa	347	7.2
19	Lexapro	555	7.2
20	bupropion	1118	7.1
21	escitalopram	783	7.1
22	fluoxetine	592	7.1
23	Prozac	381	7.1
24	Pristiq	720	7.0
25	sertraline	1071	7.0
26	trazodone	107	6.9
27	desvenlafaxine	768	6.9
28	brexpiprazole	82	6.8
29	Zoloft	545	6.9
30	Rexulti	73	6.8
31	mirtazapine	500	6.8
32	Wellbutrin SR	97	6.8
33	Effexor XR	317	6.7
34	quetiapine	161	6.6
35	paroxetine	255	6.6
36	Abilify	269	6.5
37	aripiprazole	286	6.5
38	nortriptyline	52	6.5
39	Paxil	175	6.4
40	Cymbalta	548	6.3
41	duloxetine	633	6.3
42	venlafaxine	887	6.1
43	Viibryd	554	6.1
44	vilazodone	572	6.1
45	Trintellix	530	6.0
46	vortioxetine	769	5.9
47	Zyprexa	58	5.8
48	Effexor	322	5.5
49	olanzapine	120	5.5
50	Risperidone (offlabel)	43	5.4
51	Fetzima	81	4.5
52	levomilnacipran	90	4.5

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^a10 = most effective, 1 = least effective.Data abstracted from ref (60), which contained information for a total of 101 antidepressants,not the 188 that is incorrectly listed.

^bThe following are brand names andgeneric name pairs for many of the drugs appearing in this table:Xanax and alprazolam, Parnate and tranylcypromine, Nardil and phenelzine,Deplin and l-methylfolate, Celexa and citalopram, Remeronand mirtazapine, Seroquel XL and quetiapine, Lexapro and escitalopram,Wellbutrin SR and bupropion, Prozac and fluoxetine, Pristiq and desvenlafaxine,Rexulti and brexpiprazole, Zoloft and sertraline, Effexor (and EffexorXR) and venlafaxine, Paxil and paroxetine, Abilify and aripiprazole,Cymbalta and duloxetine, Viibryd and vilazodone, Trintellix and vortioxetine,Zyprexa and olanzapine, Fetzima and levomilnacipran.

It is also interesting to mentionthat two of the four other off-labelantidepressants in Table 1 have effectiveness ratings in the “very effective”range. They include niacin (8.8) and Modafinil (8.6). Two other off-labelantidepressants, Lamotrigine (7.3) and Risperidone (5.4), had ratingsin the “Effective” and “Less Effective”range, respectively.”

Data for antidepressants with <40individual reviews was notconsidered to be sufficiently robust for comparison.

For tramadol,117 of 130 individual reviewers (90.0%) rated thismedication as very effective (rating = 8–10) (Table 2). Six reviewers (4.6%) ratedtramadol as effective (rating = 6–7) and seven reviewers (5.4%)gave it a low (less effective) effectiveness rating (rating = 1–5).Six patients provided comments, but did not provide an effectivenessrating. Thus tramadol was rated as effective or very effective by94.6% of those patients who provided ratings.

Table 2

PatientRatings for the Effectivenessof Tramadol to Relieve Depression

patient rating^a	percent	numberof patients providing this rating
10	66.2	86
9	14.6	19
8	9.2	12
subtotal 8–10 (very effective)	90.0	117

7	3.85	5
6	0.77	1
subtotal 6–7 (effective)	4.6	6

5	0.77	1
4	0.77	1
3	1.54	2
2	0	0
1	2.31	3
subtotal 1–5 (less effective)	5.4	7

total	100	130

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^aThe average effectiveness ratingfor tramadol was 9.1 (most effective = 10, least effective = 1). Datawas abstracted from ref (59). The data presented here was recalculated and the tablewas slightly modified. Effectiveness ratings of very effective, effectiveand less effective are defined as follows. Patients’ ratingsof 8–10 were designated as very effective. In this group patientsindicated that tramadol relieved depression and typically providedvery positive comments about this medication. Patients’ ratingsof 6–7 were designated as effective. In this group patients’comments indicated that tramadol relieved depression but gave it arating lower than 8–10 because of adverse, but manageable,side effects. Patient ratings of 1–5 were designated as lesseffective based solely on the low numerical rating.

Table 3 presentscomments from: (1) ten representative patients who gave very effectiverating values (rating 8−10); (2) all patients who gave effectiverating values (rating 6−7); and (3) all patients who gavelow effectiveness rating values (rating 1−5).

Table 3

Patient Comments and Ratings Regardingthe Effectiveness of Tramadol as an Antidepressant^a

patient number	effectiveness rating
Comments for VeryEffective Ratings (8–10)
#2	10	“I experienced only adverse reactionsto SSRIs and TCAsthanks in part to being bipolar, but Tramadol has been a God sendfor my depression. I was sick and tired, literally, of trying differentmedicines only to have my mood get thrown around crazily. Tramadolworked when nothing else could touch the depression. I take it twicedaily. Could not live without it. I am so thankful that my psychiatristis open to new ideas and tried this, I only will encourage othersto try this also. Because of the Tramadol I am now recovered fromany form of self injury - I am free for over 3 years. It works. Simple.”
#4	9.0	“I towent from one antidepressant to another. SSRIs(multiple), TCAs, SNRIs. Nothing worked and like others my moods wereup and down the whole time. Twice a day Tramadol has kept me symptomfree for 5 years now. Amazing.”
#16	10	“I have been depression for over 7years but in thatshort period of time I was immediately suicidal. By “fate”I found my salvation. One day I was saying my goodbye to all as Icould not live any longer with such sadness and complete doom. I wassitting with my mom and during all the crying I told her I had a severeheadache. She only had tramadol. I took two. It saved my life thatday and is still. I had tried before and even after all kinds of othermedicines and none worked.”
#33	10	“I was given Tramadol about 12 yearsago for endometriosisand severe menstrual cramping. It has made me feel so much betteroverall...it works wonders for my mood, anxiety, and depression. Iam a better person because of this drug. I am motivated, and feelgreat...all the time. This has changed my life for the better.”
#42	10	“I havehad major depression my whole life and absolutelynone of the anti depressants worked for me, I had intermitant periodsin my life were I had suicidal thoughts but I always managed to toughit out I maintained decent employment but chronically underachievedbecause I was always fighting internal demons and social anxiety,then my children left home, I got a divorce and lost my home, suicidalthoughts were non stop no matter how hard I tried to talk myself intocoping and turning my mood around, the suicidal thoughts persistedfor 2 yrs, then I was prescribed tramadol for Fibro 50 mg twice aday, I have never felt so normal in my whole life took it 3 yrs nodose increase off it for six months too hard to get the RX now suicidal24/7”
#68	10	“Antidepressants have had no effect on my depressionin the past. I was unable to find the motivation to support my familyor even go to work which caused me to lose my job. I started tramadolfor a back injury as it is a nonhabit forming pain reliever. It changedmy life. immediately, it wiped out the depression. 100% gone. It isnot much of a pain reliever, it is not very strong and I still amin pain. I can deal with it though and the lack of depression is worthit. The only downside is that when it wears off the depression comesright back, fast. So I have to take it throughout the day. I am backto work and enjoying life, i just take 3 or 4 pills per day. I donot know why this drug is not marketed as an antidepressant, it shouldbe.”
#8	9	“I have been on Tramadol (50 mg 3× per day) forabout 6 years now. For the first few years is was a miracle cure.I have struggled with depression/anxiety/impulse and obsessive disordersmy entire life. This made me finally feel free and human for the firsttime ever. The only downfall was after a few years, the effects woreoff, and slowly my depression/anxiety began to creep back in. I tooka break from it for a few months (warning: withdrawing from Tramadolis reallllly uncomfortable). I went back on it after my Dr assuredme it was a good med (even long-term) for fibromyalgia/depression,etc. I’m up to about 4/day now. It still helps, but not nearlyas much in the beginning.”
#112	9	“I have taken tramadol off and on for3 years for hipbursitis and I also have suffered from depression for the last 30years. When I take it I feel any signs of depression lift...I feelmotivation to engage in life, my mind feels clear, and I have moreenergy. I recently had an honest conversation with my psychiatristabout using low dose tramadol for depression. I’ve tried adozen different antidepressants with ton of side effects and hardlyany good long lasting results. I do not feel any side effects fromthe tramadol and 50 mg can last me all day. I do notice when it wearsoff but I do not mind as I’ve had a good 8 h feeling normal,not high. I am hopeful now. I’ve been able to just stop itwithout side effects when needed to so far...its such a low dose butdoes wonders.”
#102	8	“I got prescribed Tramadol for Back pain.I have beentaking one 50 mg pill a day and have seen such an enhancement in mymood. I’ve never wanted to take “antidepressants oranxiety” meds, because I did not want it to change my personalityor make me a zombie. However, I really enjoy being on Tramadol, itmakes my job in retail not such a drag. I do not have my normal moodswings, and by then end of the night I sleep great! I am afraid totell my doctor as well that it helped me in that aspect because Ido not want her to think I’m using it as a “high.”But I genuinely love this medication.”
Comments for EffectiveRatings (6–7)
#74	7	“Tramadol is NOT anopiate. It does act on the samepain receptors as opiates, but it does not have the same addictivequality as opiates and does not have the same risk of abuse as opiates.You can become dependent on Tramadol, just as you can be dependenton SSRI’s. You cannot cold turkey quit an SSRI without somereally gnarly withdrawal symptoms and the same goes for Tramadol andopiates and tons of other drugs. I’ve been taking Tramadolfor 4 years for general pain in my body due to end stage renal diseaseand osteodystrophy. Since I’ve been taking Tramadol I havenot needed antidepressants and I find that I function at a higherlevel with Tramadol than with any SSRI I have ever taken. There areno negative side effects for me.”
#36	7	“For sure tramadol is oneof the best drugs for Depressionand Anxiety. I have tried a lot of differents antidepressives likefluoxetine, sertraline, paroxetine, citalopram, escitalopram, venlafaxine,etc., and they all did not work very well for my depression and anxiety.I suffered a lot of side effects with these drugs. The only one thatreally works for depression and anxiety, for me, is Tramadol···but··· but··· it destroyed my sexuallife··· Who is using this drug for depression willfeel much better, for sure, but, please, be aware of your sex life!For sure, when I take Tramadol my libido goes to ZERO, and I can notkeep an erection for some time··· and, if a keep, itis impossible to ejacul*te··· That is why a give a7···”
#80	7	“The comments resonate with me regards Tramadol.I wasdiagnosed it for back pain which it relieved and gave me a surge ofenergy and wellbeing which later disappeared with use, but it is stilluseful for relieving my dire morning depression, if taken 2 h beforerising I can face getting out of bed.”
#35	7	“Very affective for anxiety,but made me so tired Ihad to switch.”
#25	7	“Tramadol is about the most effective drugin the worldfor depression - for immediate, short-term relief ONLY though. Duringthe initial dosing period, 100 mg twice a day utterly obliteratesany negative thinking or depression symptoms. It delivers resultsimmediately, vs the necessary patience of waiting a few days or weekswith traditional SSRI drugs. However, tolerance DOES build to tramadaolat a pace far more rapidly then with traditional antidepressants.I had 2 months of solid relief from 100 mg 2x daily, but by the thirdmonth this does barely made a difference and my mood continued tosink. Instead of upping my dose, I went back on Zoloft which deliversless immediate, but more consistent long-term results for me.”
#116	6	“Theregood for pain.”
Comments for Less(i.e., Low) Effective Ratings (1–5)
#108	5	“goodfor very intermittent use–be careful extremelyaddicting”
#111	4	“I placed a post earlier on 2019–07–10 under the name Jerry saying – I was a 65 year old male thattakes Tramadol intermittently to reduce depression. the problem isthat when I do take days off – I am extremely depressed 3 timesas much. So you have to be very careful of this medication.”
#69	3	“I seea recurring theme in a lot of these entries...(person x) was prescribed Tramadol for pain, and it did wonders fordepression and mood. However, when discontinuing use, one’ssymptoms quickly return, often worse than before... Tramodol is anOPIATE. Think Opium, Heroin, Oxycodone, Hydrocodone, Codeine, etc.What you are describing is the pattern of Opiate usage and it is dangers.This is why it is a poor choice for depression treatment - it is likegiving a Mercedes to a guy who’s lost his job and his houseis being foreclosed on...feels good for a couple days, but...”
#84	1	“This medicationwas initially prescribed for back pain.As an unexpected side effect it dealt with my MDD perfectly. UnfortunatelyI am medication sensitive and started to have negative side effectsso had to slowly get off this medication. For some reason the withdrawalwas horrible. Everybody responds differently and even though thismedication worked with the pain and depression it’s side effectsmade it impossible for me to remain on it and the withdrawal was theworst part ‘for me.’”
#94	1	“Doesnt do a thing for me,”
#134	3	“The tramadolhelped my depression for a while. I tookit on at off (50 mg per day) with various antidepressants. I wouldfeel effects about 2 h in, but they would fade quickly - and theynever fully took away symptoms. I then started taking 2 (50 mg) perday - one before getting up to help morning mood and then one laterin the day. This was not effective at all. I’ve now been onthe 2× per day dose for a month and am tapering down to 1 perday for a week, then will go to 1/2 per day for a week and stop. I’mgoing to try pregabalin as my depression has some anxiety and thatmight help?”
#138	1	“Took first dose 2 years ago. Was 1 year sober (alcohol)and took unprescribed for pain. Took 2 weeks to go 300 mg/day. Sixmonths later at 800 mg/day; had 2 seizures. After I maintained at600 mg/day for 8 months. Was happy, energetic, and productive. Wantedout, not willing to give up benefits. Then pandemic came/shut downmy source. Self-tapered, now at 100 mg/day, cannot taper further withoutphysical withdrawal. Altered mental state to point of suicidal ideationsduring taper. Works as antidepressant, very addicting. Wish had nevertaken. I read these forums when I first started experimenting andthought I could manage it. I was wrong. I guess it treats everyonea little differently, but if this post could persuade one person toget out of it before it is too late then I have my purpose for posting.Please be very careful with this drug, I am still in so much psychologicalpain unlike anything I’ve experienced since getting sober.”

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Table 4

Length of Time PatientsUsed Tramadolto Treat Depression^a

time	number of patients	%
10 or more years	4	4.5(4.494)
5–10 years	14	15.7(15.730)
2–5years	23	25.8(25.843)
1–2 years	14	15.7(15.730)
0.5–1 year	6	6.7(6.742)
1–6 months	22	24.7(24.719)
less than 1 month	6	6.7(6.742)
total responding	89	99.8(100)

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^aData was abstractedfrom ref (59).

As noted in Table 5, entries f–h, 6 patients assertedthat tramadol relievedsymptoms associated with bipolar depression. Consistent with publishedreports,^44,52 4 patients asserted that tramadol relieveddepression associated with post-traumatic stress disorder, and 5 patientsreported relief from treatment resistant depression.

Table 5

Analysis of Tramadol Consumption forDepression: Descriptors and Queries^a

	descriptors and queries	comments
(a)	patient’s age and gender	Limitedpatient response to these descriptors allowed onlythe general observation that adult males and females were includedin the group of patients providing reviews.
(b)	How long has patient hadto deal with depression?	Nine patients reported dealingwith depression for a decadeor more. Two asserted that they have dealt with depression for over40 years.
(c)	How rapidly does tramadol work?	Nineteen patients notedthat tramadol was a fast-acting antidepressant.
(d)	What was the patient’sassessment regarding efficacyof tramadol relative to other antidepressants; was tramadol superior?	Sixty-three patients explicitly or implicitly noted that theyhad tried other antidepressants and found them lacking, in comparisonto tramadol. Eight patients reported taking tramadol with other antidepressants.
(e)	Were physicians,psychiatrists, and other healthcare providerswilling to prescribe tramadol?	Physician awareness oftramadol’s effectiveness as anantidepressant and their willingness to prescribe tramadol as an antidepressantvaried considerably.
(f)	Was tramadol effective for bipolar depression?	Six patients asserted that their depression was associatedwith bipolar disorder and that tramadol relieved their symptoms.
(g)	Was tramadol effectivefor treatment-resistant depression?	Five patients assertedthat their depression was treatment-resistantand that tramadol relieved their symptoms.
(h)	Was tramadol effective forpost-traumatic stress disorder (PTSD)?	Four patientsreported that they suffered from depression associatedwith post-traumatic stress disorder (PTSD), and one patient thoughthe/she might be suffering from this affliction. All five patientsreported that tramadol relieved their symptoms.
(i)	Was tramadol’s effectivenessfor depression discoveredwhen this medication was used for pain?	Half (68/136)of the patients reported the serendipitous discoveryof tramadol’s effectiveness as an antidepressant after it wasinitially used for pain.
(j)	Did depression return following cessation?	Eighteen patients reported that they experienced a return ofdepression when they stopped taking tramadol.
(k)	Was withdrawal problematic?	Eleven patients reported that they experienced withdrawal uponcessation of tramadol.
(l)	Was addiction a concern?	Twenty patients providedcomment or opinion regarding the possibleaddictive potential and withdrawal effects of tramadol.
(m)	Did addiction or dependenceactually occur?	Four patients explicitly or implicitlyacknowledged being addictedto tramadol. Three patients asserted they were dependent but not addicted.
(n)	Was a buildupof tolerance observed?	Three patients asserted or impliedthat tolerance was a problemfor them.
(o)	Was fatigue a side effect?	Two patients reportedthat tramadol made them tired.
(o)	Did tramadol affect sleep?	Only one patient reportedthat tramadol interfered with sleep.In contrast, 5 patients reported that they slept well while takingtramadol, and 20 patients reported that tramadol made them more energetic.
(p)	Was decreasedlibido a side effect?	Five patients reported loss orreduction of libido as a significantside effect.
(q)	Was tramadol an effective analgesic?	Ten patients notedthat tramadol was, in general, only a marginallyeffective or noneffective analgesic but continued taking it becauseit relieved their depression.
(r)	Were adverse side effects (seizures or serotoninsyndrome)encountered?	In the patient reviews, only one reportedhaving seizures uponprolonged use at supratherapeutic doses. No patient reported experiencingserotonin syndrome.
(s)	Did patients find it difficult to obtain a prescription?	Twenty-nine patients commented about the unwillingness of healthcareproviders to prescribe, or continue prescribing, this medication fordepression.
(t)	Did tramadol relieve suicidal ideation?	No patientreported experiencing suicidal ideation or thoughtsof self-injury as a result of taking tramadol. Thirteen patients reportedthat depression associated with suicidal ideation or thoughts of self-injurywere relieved as a result of being treated with this medication. Sixpatients experienced or feared a return of suicidal ideation uponcessation of tramadol.
(u)	What other side effects were encountered?	Thereare a host of minor side effects that have been associatedwith tramadol administration. See text for further information,

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^aA more extensive and detailed versionof this table is presented as Table S-2 in which patient numbers are provided, thus allowing the readerto locate specific patient comments which appear in Table S-1.

Six patientsgave effective ratings of 6 or 7. Four patients acknowledgedthat tramadol relieved their depression and provided very positivecomments. In general, these patients gave ratings lower than veryeffective because of adverse, but apparently manageable, side effects(e.g., “really gnarly withdrawal symptoms”, loss oflibido, and buildup of tolerance) that were experienced. Two patientsin this group did not provide comment regarding depression.

Seven patients provided ratings and comments in the less effectiverange (1–5). Five of these patients still acknowledged thattramadol relieved depression. One patient found it to be ineffective.One patient found that tramadol’s antidepressant effects woreoff quickly, and elected to taper off and try another antidepressant.Most patients in this group gave tramadol low effectiveness ratingsbecause of unacceptable adverse side effects.

Of the cohortof 136 patients, 63 patients (46.3%) reported thatthey had tried other antidepressants and found them lacking, in comparisonto tramadol (Table 5, entry d). Other antidepressants mentioned by patients are presentedin Table S-2, entry d. Half (68/136) ofthe patients reported the serendipitous discovery of tramadol’seffectiveness as an antidepressant during its use as an analgesic(Table 5, entry i).Ten patients noted that tramadol was, in general, only a marginallyeffective or noneffective analgesic but continued taking it becauseit relieved their depression (Table 5, entry q).

Discussion

Addiction,Dependence, Abuse, or Successful Treatment?

Tramadol wasintroduced to the market as a nonscheduled drug in 1995with the caveat that a surveillance program be put in place to monitorfor the possibility of high levels of abuse.¹ On the basis of available data, which at that time did not detectsubstantial abuse, tramadol continued to be marketed for the restof the 1990s and early 2000s as an unscheduled drug. However, monitoringbetween 2003 and 2009 revealed an increase in the incidence of diversion,abuse and overdose of this medication, leading Arkansas, Kentucky,Tennessee, and Wyoming to change the drug from unscheduled to ScheduleIV.¹ The federal government rescheduledtramadol as a Schedule IV drug in 2014.¹

Patients’ comments (Table 5, entries l and m) regarding addiction toand dependence on tramadol are consistent with the CriticalReview Report: Tramadol(1) by theWorld Health Organization’s Expert Committee on Drug Dependencein 2018, who reported the following: “The developmentof physical dependence from tramadol therefore appears dose-related,and administration of 800 mg/day tramadol leads to similar levelsof opioid physical dependence as 60 mg/day morphine.”(1) The Expert Committee further statedthat differences exist between high and low dose use of tramadol andthat unlike those who used high dose tramadol the risks of “...physical dependence and withdrawal symptoms were lowerthan prototypic opioid effects...”(1) for those who used low-dose tramadol over an extended periodof time. Patients’ reviews analyzed here (Table 6) demonstrate a clear preference(79.2%) for using low doses (25–150 mg/day) of tramadol totreat depression. This appears to be due to good medical practice,physicians prescribing the lowest effective dose, and some degreeof self-selection by patients in favor of low-dose regimens.

Table 6

Dose of Tramadol Consumed by the 72Patients Who Reported Dose^a

dose (mg/day)	number	patient number^b
>400	2	#129, #138
400	3	#45, #106, #137
300	3	#7, #135, #139
200	7	#8, #15, #18,#20, #25, #31, #70
150	8	#6, #22, #28, #32, #50, #86, #91, #126
125	1	#98
100	25	#2, #4, #14, #16, #19, #23, #26, #27, #38,#42, #43, #44, #60,#63, #76, #79, #89, #95, #117, #119, #122, #127, #133, #134, #136
50	21	#10, #17, #30,#34, #41, #66, #71, #73, #78, #85, #88, #93,#99, #100, #102, #104, #110, #112, #121, #123, #130
25	2	#77, #96
total	72

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^aData was abstracted from ref (59).

^bIn some reviews,patients reportedthey took varying doses. Patients #96 took 25 or 50 mg/day. Patients#27, #95, #117, and #127 took 50 or 100 mg/day. Patient #8 took 150or 200 mg/day. Patient #91 took 100 or 150 mg/day. Patient #20 took100 or 200 mg/day. Patient #129 took up to 800 mg/day but “tapereddown”. Patient #138 took from 100 to 800 mg/day. For the purposesof this table, the larger values were used except for Patients #50,#77, and #96. For Patient #50, the lower value was used because he/sheindicated that was the typical dose. For Patients #77 and #96, thelower value was used because this value (25 mg/day) was representativeof what appeared to be the lowest dose at which patients found tramadoleffective in ameliorating symptoms of depression. Patient #96 tookthis medication only 4 days/week. Patient #89 took 100 mg/day foronly 3 or 4 days/week. When patients reported dose in the number oftablets consumed, each tablet was considered to be equal to 50 mg.

Dunn et al.⁶³ recently reviewed andcompared the abuse potential of tramadol with other opioid receptoragonists. It was concluded “...that tramadol confersan equal or lower risk of abuse than the opioids to which it was compared,that its greatest risk for abuse is when it is being administeredvia oral formulations to non-dependent individuals, and that the likelihoodit will be abused appears to decrease as the dose increases or whenit is administered parenterally.” Dunn et al.⁶³ further concluded that “The presentliterature therefore suggests that the human abuse potential of tramadolis different from and lower than other opioid agonists.” Dunn et al.’s⁶³ analysis notedthat in two of three studies oral administration of tramadol producedmore “...bad effects as the dose increases...”, and this may be the reason why “...the likelihoodit will be abused appears to decrease as the dose increases...”.⁶³ Therefore, in the present analysis,it is reasonable to suggest that the majority of patients (Table 6) consumed a low doseof tramadol not only because it was effective at low doses but alsobecause higher therapeutic (and supratherapeutic) doses produced more adverse (i.e., “bad”) effects.

The recreational abuse and/or addiction to supratherapeutic dosesof tramadol is an important public health issue and requires appropriatemedical and regulatory intervention, especially in countries whereits use is unregulated.¹ Discussion ofthe addictive and/or dependent nature of tramadol is, however, confoundedby the reality that in an appropriately supervised clinical settinglong-term relief from depression (i.e., mood enhancement) is the clinicalgoal. In such a setting, it does not seem appropriate to view long-termreliance/dependence on therapeutic low doses of an effective medicationin the same pejorative context as addictive recreational abuse/useof supratherapeutic doses. Discussion of addiction and dependenceis further confounded because cessation of tramadol in clinicallydepressed patients may result in a return of their depression andother symptoms (i.e., antidepressant discontinuation syndrome)^64,65 that make it difficult to distinguish from withdrawal caused bycessation of a drug to which the patient may be truly addicted.

Physician Awareness and Willingness to Prescribe Tramadol forDepression and Patients’ Concerns Regarding Access to Tramadol

As noted in Table 5, entries e and s, patient reviews demonstrated that physician awarenessof and willingness to prescribe tramadol as an antidepressant variedconsiderably. Some physicians accepted the patient’s observationsthat tramadol relieved their depression and continued prescribingthis medication. Others were less willing to do so. Tramadol’sdocumented potential for abuse, the opioid epidemic, it is reclassificationas a Schedule IV drug,¹ and a lack of awarenessof its effective off-label use as an antidepressant are likely reasonsmany healthcare providers are reluctant to prescribe this medicationfor depression. Twenty-nine patients commented about the unwillingnessof healthcare providers to prescribe, or to continue prescribing,tramadol for depression. An unfortunate consequence is that denialof this medication may result in the perception of “doctor-shopping”and be interpreted as “drug-seeking behavior”, whenin reality the patient is seeking an effective medication for depression.For 18 patients, this did indeed prove problematic when patients encounteredthe unwillingness of healthcare providers to prescribe or renew prescriptionsfor tramadol to treat depression. This was/is particularly worrisomefor six patients who experienced or feared a return of suicidal ideationupon cessation of this medication (Table 5, entry t).

A related issue concernspatient–physician communication. A few patients reported problemsor hesitancy explaining to their physicians that tramadol prescribedfor pain actually relieved their depression because it was fearedthey would stop prescribing this medication. Cleary misunderstandingand lack of communication is problematic for these individuals. Patientsshould be able to communicate their observations to physicians withoutfear that an effective medication will be withdrawn.

Other IssuesConcerning Possible Adverse Side-Effects

Misuse, Overdose, and Suicide

Tramadol abuse has beenwell-documented and is clearly a problem and a major reason why itwas reclassified as a Schedule IV drug.¹ Equally well-documented is the involvement of tramadol overdosein intentional and unintentional suicides.¹ However, there is very little evidence suggesting that tramadol per se causes suicidal ideation. Only one short report wasfound suggesting tramadol was the cause of depression associated withsuicidal ideation in one patient.⁶⁶ Inthe analysis presented here 13 patients reported tramadol relievedsuicidal ideation that was associated with their depression (Table 5, entry t) which isconsistent with five published investigations.^{33,36,37,44,47} It should be noted, however, that current guidelinesrecommend against prescribing this medication for patients with existingsuicidal ideation.⁶⁷ This apparent inconsistencyrequires further scrutiny.

Seizures and the Serotonin Syndrome

Seizures and serotoninsyndrome are the most serious and potentially lethal complicationsassociated with the use of tramadol.^1,68−80 Thus, it is important to view the risk of these complications inproper perspective. Seizures and/or serotonin syndrome have been reportedto occur even when therapeutic doses of tramadol have been ingested.^68,73 Idiosyncratic observations like these are important to consider.Nevertheless, the overwhelming incidence of tramadol associated seizuresand serotonin syndrome are from overdoses due to suicide attempts,recreational use/abuse of supratherapeutic doses and interaction withdrugs (e.g., antidepressants and/or monoamine oxidase inhibitors)that potentiate the occurrence of these complications.

The incidenceof seizures associated with tramadol has been estimated to be 0.15and 0.86%,^79,80 and reputable drug advisory sitesregard the occurrence of seizures, in therapeutic doses, as “lesscommon”⁸¹ or “rare”,⁸² with one⁸³ estimatingthat the risk was less than 1%. Furthermore, the Johns Hopkins UniversityPeripheral Nerve Center⁸⁴ estimates therisk of seizures due to tramadol to be less than 1 in 100 000.Finally, the World Health Organization Tramadol Update Review Reportin 2014 stated that “Rarely, seizures occur at therapeuticdoses of tramadol.”(85) Patientreviews are consistent with this. Only one patient (#138)) reportedhaving seizures upon prolonged use of supratherapeutic doses. Theincidence of serotonin syndrome is not known. However, it appearsto be even less frequent than that of seizures.^69,70 No patients in this analysis reported having to deal with serotoninsyndrome.

Most reviews by patients indicated that low-dose tramadolalonewas sufficient to successfully treat depression (Table 6). However, eight patients usedtramadol in combination with another antidepressant (Table 5, entry d). Thus, the questionremains, “Is it advisible to prescribe tramadol in combinationwith another antidepressant?” Park et al.⁸⁶ concluded “Tramadol is only contraindicatedin combination with MAOIs but not other antidepressants in commonuse today... Tramadol can be safely combined with antidepressants;however, monitoring and counseling patients are prudent when startinga new serotonergic agent or when doses are increased.”(86)

Other Potential SafetyConcerns

Continued Use

Two research groups recently reportedthat some patients who were tramadol-naïve and/or had not usedtramadol before surgery continued consumption of this medication (doseunknown) for several months following its use to treat pain aftersurgery.^87,88 No information was presented by the authors,in either study, concerning why patients continued to take this medication.Thus, in lieu of other information, it is reasonable to suggest thatpatients did so under the continued supervision of a physician whoappropriately prescribed tramadol for chronic pain and/or depression.In the investigation by Thiels et al.,⁸⁷ it is interesting to note that in the group (n =13 519) receiving tramadol only 194 (1.44%) and 78 (0.58%)were considered persistent or chronic users, respectively. These smallnumbers and percentages of persistent or chronic users are of interestto the current analysis when one considers that 460 (3.4%) patientsin the study by Thiels et al.⁸⁷ were experiencingdepression as a comorbidity prior to surgery. Thus, it is reasonableto suggest that like many (68/136, 50.0%) of the patients in the analysispresented here some of the patients in the study by Thiels et al.⁸⁷ continued to take tramadol because they toomade the serendipitous discovery of this medication’s effectivenessas an antidepressant during its use as an analgesic.

All-CauseMortality

The possible association of tramadolwith all-cause mortality has also been investigated.^89,90 Assessing the association of a drug with all-cause mortality isoften a difficult and controversial endeavor. For example, Zeng etal.⁸⁹ reported that in a population limitedto patients with osteoarthritis over 50 years of age, all-cause mortalityassociation was greater for tramadol when compared to naproxen, diclofenac,celecoxib, and etoricoxib but not with codeine. However, Felson⁹¹ and Manchikanti et al.⁹² as well as Zeng et al.⁸⁹ in their originalreport and in a response by three of the authors⁹³ noted that “...these findings may be susceptibleto confounding by indication, and further research is needed to determineif the association is causal.”⁹³ Manchikanti et al.⁹² furtherasserted that “...this study was based on a complexstatistical model, had many inconclusive findings and was statisticallyunderpowered making it far from precise.” A similarconclusion was reached by Kloppenburg and Berenbaum.⁹⁴

In another recent investigation, Musich et al.,⁹⁵ reported that a small increase in all-causemortality and other adverse effects may be associated with tramadolconsumption compared to nonusers. When compared to other opioids,tramadol users (older adults (≥65)) had fewer adverse eventrisks. However, tramadol users had higher risks than patients whodid not consume opioids. Interestingly, Musich et al.⁹⁵ also reported that a small increase in all-cause mortalitywas statistically significant for new users but not for patients takingtramadol long-term. This is of interest to the current analysis as55 of 89 (61.8%) patients who reported the length of time they usedtramadol to treat depression report having used this medication fora year or more, four patients for over a decade.

Other SideEffects

Interference with sleep or fatigueis one of the side effects thought to be caused by tramadol.⁸¹ In the present analysis, two patients reportedthat tramadol made them tired. Only one patient reported that thismedication interfered with sleep. In contrast, four patients reportedthat they slept well while taking tramadol, and 19 patients reportedthat tramadol made them more energetic. There are a host of minorside effects that have been associated with tramadol administration.⁸¹ The following side effects were reported byonly one patient each: constipation, headache, nausea if not takenwith food, short-term memory loss upon cessation, and hot flashesat night. Three patients reported that tramadol helped them to loseweight. Two patients reported that tramadol helped him/her quit drinkingalcohol, and one patient reported that this medication helped him/herquit both drinking alcohol and smoking.

The analysis providedhere shows that, in the patient population submitting reviews anddose consumed, tramadol at low doses is an effective medication formost patients. This analysis also suggests that with regard to themost important and serious potential adverse side effects tramadolat these low doses is a generally safe medication. Nevertheless, forsome patients, there may be adverse risks, and idiosyncratic responseshave been reported^{66,73,86,96,97} for this medication.Thus, further clarification is needed to determine the level and incidenceof such risks, especially the possible differences in risk and adverseeffects (including possible association with all-cause mortality)within the therapeutic range between low dose (25–150 mg/day)and high dose (151–400 mg/day) tramadol.

Summary,Conclusions, and Observations

In 139 reviewswritten by 136 patients, tramadol was reported to be an effectiveor very effective antidepressant for 94.6% (123/130) of the patientswho submitted ratings to drugs.com.⁵⁹ Significantly, most (57/72, 79.2%)patients who reported dose consumed experienced relief from depressionat low therapeutic doses (25–150 mg/day). When compared tothirty-four other antidepressants in the database titled DrugsUsed to Treat Depression,⁶⁰ forwhich there were ≥100 individual reviews for each drug, tramadolwas rated by patients as being the most effective (effectiveness rating= 9.1/10) and was one of only two antidepressants to have a very effectiverating (8.0–10.0) coupled with ≥100 individual reviews.Patient reviews coupled with a review of the literature indicate thatwhen taken in low therapeutic doses under the supervision of a healthcareprovider in the absence of drugs known to cause adverse interactions(specifically monoamine oxidases and serotonin reuptake inhibitors)tramadol is a generally safe, effective, and fast-acting medicationfor relief from depression. This analysis is translational in thesense that it provides a rationale and knowledge-base for physiciansto consider including tramadol in the arsenal of medications availableto them for treating depression, especially in those patients forwhom other antidepressants have not been effective.

Supporting Information Available

The SupportingInformation isavailable free of charge at https://pubs.acs.org/doi/10.1021/acsptsci.0c00132.

All patient comments andratings regarding the effectivenessof tramadol as an antidepressant; analysis of tramadol consumptionfor depression: descriptors and queries (PDF)

Notes

The author declares nocompeting financial interest.

Supplementary Material

pt0c00132_si_001.pdf^{(188K, pdf)}

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Articles from ACS Pharmacology & Translational Science are provided here courtesy of American Chemical Society

Low-Dose Tramadol as an Off-Label Antidepressant: A Data Mining Analysis from the Patients’ Perspective (2024)

Associated Data

Abstract

Methodology

Selection of the Medical Social Media WebsiteUsed in This Analysis

Analytical Approach

Data Mining

Limitations and Strengthsof This Analysis

Results

Effectivenessof Tramadol as an Antidepressant

Table 1

Table 2

Table 3

Table 4

Table 5

Discussion

Addiction,Dependence, Abuse, or Successful Treatment?

Table 6

Physician Awareness and Willingness to Prescribe Tramadol forDepression and Patients’ Concerns Regarding Access to Tramadol

Other IssuesConcerning Possible Adverse Side-Effects

Misuse, Overdose, and Suicide

Seizures and the Serotonin Syndrome

Other Potential SafetyConcerns

Continued Use

All-CauseMortality

Other SideEffects

Summary,Conclusions, and Observations

Supporting Information Available

Notes

Supplementary Material

References